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In an ongoing effort to address ways of understanding the mechanisms underlying devastating lung diseases such as cystic fibrosis, researchers at Massachusetts General Hospital have developed a stepwise method for generating disease-specific lung progenitor cells and airway epithelial tissue starting with skin cells from patients with cystic fibrosis. These cells can provide a platform for screening potential therapeutic compounds for humans and for studying lung disease.

The team, led by Jayaraj Rajagopal ’94, an HMS assistant professor of medicine at Mass General and a faculty member at the Harvard Stem Cell Research Institute, refined the serial method in a mouse model, beginning with murine pluripotent stem cells that were then converted to lung progenitor cells in a manner that mimicked how embryonic cells are converted into lung cells in an embryo. When placed subcutaneously in mice, the progenitor cells formed airway epithelium. The scientists then applied the technique to human cells by creating induced pluripotent stem cells (iPSCs) from skin cells taken from patients with cystic fibrosis. Among the iPSCs created, one was generated from a patient who carried two mutations known to cause cystic fibrosis; each of the mutations has been a target for therapeutics. When these disease-specific lung progenitor cells were grafted into an immunodeficient mouse model and allowed to replicate, they developed into human airway epithelium.

The researchers hope to use the stem cell–generated lung epithelial tissue to study cystic fibrosis further and to screen drugs to find ones that work best for individual patients. In addition, the technique can be used to study and screen therapeutics for other diseases that affect the lung’s epithelium, including asthma, lung cancer, and chronic bronchitis.